Congestive heart failure (CHF) is a leading cause of morbidity, mortality, and hospitalization in women. The observation that women with nonischemic cardiomyopathy have an age-related increase in mortality suggests that postmenopausal estrogen loss may alter the phenotypic expression of CHF. Because estrogen is a potent in vitro inhibitor of pro-inflammatory cytokines (e.g., TNFa, IL-1B, IL-6), which are re-expressed by the failing myocardium in patients with CHF and are related to an adverse prognosis, we postulate that estrogen replacement will improve the outcome of postmenopausal women with CHF. This hypothesis is supported by our preliminary data that demonstrate 1) female sex confers a survival advantage in transgenic mice with CHF due to over-expression of TNFa, 2) female sex is associated with an attenuated pathologic response of cardiac myocytes to TNFa, 3) estrogen and progesterone inhibit TNFa production by rat cardiac myocytes, 4) estrogen replacement therapy in postmenopausal women with CHF abrogates an age-related increase in TNFa, and 5) estrogen therapy in women with severe CHF is associated with a significant decrease in mortality. Our proposed randomized placebo-controlled double-blind study of hormone replacement therapy in women with CHF will evaluate the hypothesis that estrogen has a protective effect in postmenopausal women with CHF related to modulation of TNFa and associated "downstream" cytokines (i.e., IL-lB. IL-6) and/or myocardial expression of cytokine receptors. We plan to compare the effects of hormones on functional capacity, biventricular mass and function, and quality of life with their effects on circulating cytokines in postmenopausal women with CHF. To determine the degree of hormone-induced cytokine suppression that is associated with favorable outcome, we will compare post-treatment cytokine levels in women with CHF with cytokine levels in a "control" group of women from the NHLBI WISE study who have no evidence of CHF and normal ventricular function. The results of this study will define the mechanism of estrogen's beneficial effect in postmenopausal women with CHF.